The goal of the proposed research is to develop a novel method of noninvasive light delivery for optogenetics. Successful completion of this project will enable us to perform functional mapping of the brain in vivo which will illuminate our understanding of the brain in new and exciting ways. The central obstacle to focusing light within tissue is the opacity of tissue in the optical regime. This opacity is mainly due to the strong scattering nature of tissue in the optical regime, which dwarfs the effects of absorption by 2-3 orders of magnitude. In much the same way as fog diffuses car headlights, tissue deflects incident light in a multitude of directions. If this scattering effect of tissue could be turned of, the human body would effectively behave as if it were translucent like a jellyfish. While this scattering may seem to be random, it is in fact a deterministic process. As a consequence of this fact, if the amplitude and phase of a light field exiting a scattering sample can be recorded and its optical phase conjugated wave back-propagated into the sample, the optical phase conjugated (OPC) wave will retrace the path of the original wave and reproduce the original light field. Prof. Yang's group has been developing a technology to exploit this discovery called digital time- reversed, ultrasound encoded light delivery (TRUE). This approach records the scattered light field and back-propagates the wave into the sample using an ultrasound focus at a point within the tissue to target a specific voxel. This technique has been demonstrated at depths up to 4 mm. My proposed project will continue to develop this technology to improve its maximum working depth and efficiency so that it can be used to activate or inhibit neurons within the brain using optogenetics. This challenging goal will be accomplished through three specific aims: (1) Improve the response time of the system to adequately adapt to changes in live tissue, (2) Convert the system from the current transmission based system to a reflection geometry to enable noninvasive operation, and (3) Test and optimize the digital TRUE system first using embedded fluorescent microbeads in rodent brain slices and finally activating specific neurons in the brain to demonstrate the feasibility of this technology for optogenetics in vivo. Successful completion of these goals will serve as a powerful demonstration of the capabilities of the digital TRUE system and enable functional brain mapping in vivo in a way that has never before been possible.